Category: Chest Pain

hsTnI – All Promise, No Proof

At some point, it is true – there are no “bad” tests, only “bad” applications and interpretations of those tests.  One of those tests, as supported by Abbott Laboratories, is the high-sensitivity troponin.  You may also know this test as the “low-specificity” troponin – as, barring small improvements in the assay, a more sensitive test for the same biomarker is bound to result in decreased specificity.

This article describes the populations of ADAPT and APACE for whom high-sensitivity troponins are available.  These trials were part of a prospective derivation of an “accelerated diagnostic protocol,” in which low-risk patients (TIMI 0 or 1) with normal ECGs and two negative hsTnI two hours apart were found to be eligible for discharge from the Emergency Department.  With an approximately 14% of 30-day MACE (mostly nSTEMI) in each cohort, the authors strategy is reasonable:  only ~0.7% of patients meeting these three criteria eventually met a primary endpoint.

Conversation about this article led to this tweet by the primary author:

@EMManchester @240minDoc Precision of hs #troponin assays now shown to have great advantage. ED patients with possible ACS and this assay 1
— Louise Cullen (@louiseacullen) November 7, 2013

… except it isn’t entirely true.  The missing key to this statement is precisely what the “great advantage” entails.  These authors, sponsored by Abbott Laboratories, do not show this diagnostic strategy utilizing hsTnI is in fact superior to the same strategy using conventional troponins.  Quick back-of-napkin math shows the ADAPT conventional troponin cohort using this same strategy gives statistically similar results.  This critique led to the final tweet from the primary author:

@emlitofnote @EMManchester @240minDoc OK have to wait til part II where I can show you larger pop and more narrow CIs.
— Louise Cullen (@louiseacullen) November 8, 2013

Yes, with sufficient statistical power, there will likely be a reproducible difference between the different troponin assays.  When millions of patients are evaluated for chest pain every year, there may be a few for whom this improved sensitivity is clinically significant.  However, it is far more likely this increased sensitivity will end up referring additional patients for testing – resulting in increased costs and harms from overdiagnosis.  This is not the fault of the test – but, rather, simply that we don’t yet know the clinical significance of all small troponin elevations, and there is no appropriate algorithm for managing them in current practice.

I actually like what these authors are doing – using a rapid rule-out plus risk-stratification to safely discharge patients from the Emergency Department.  However, they’re selling hsTnI without proving it’s superior, in this strategy, to conventional troponin testing.  Then, as tests become more sophisticated, our interpretation of them needs to as well – and studies such as these need to do more than simply describe a “minimal-risk” cohort, but also provide useful guidance on the rest of the grey area troponin elevations.

Finally, I’d also like to finally see the TIMI score retired for use in the Emergency Department.  Please. Make it die.

“Validation of High-Sensitivity Troponin I in a 2-Hour Diagnostic Strategy to Assess 30-Day Outcomes in Emergency Department Patients With Possible Acute Coronary Syndrome”

Replace Us With Computers!

In a preview to the future – who performs better at predicting outcomes, a physician, or a computer?

Unsurprisingly, it’s the computer – and the unfortunate bit is we’re not exactly going up against Watson or the hologram doctor from the U.S.S. Voyager here.

This is Jeff Kline, showing off his rather old, not terribly sophisticated “attribute matching” software.  This software, created back in 2005-ish, is based off a database he created of acute coronary syndrome and pulmonary embolism patients.  He determined a handful of most-predictive variables from this set, and then created a tool that allows physicians to input those specific variables from a newly evaluated patient.  The tool then finds the exact matches in the database and spits back a probability estimate based on the historical reference set.

He sells software based on the algorithm and probably would like to see it perform well.  Sadly, it only performs “okay”.  But, it beats physician gestalt, which is probably better ranked as “poor”.  In their prospective evaluation of 840 cases of acute dyspnea or chest pain of uncertain immediate etiology, physicians (mostly attendings, then residents and midlevels) grossly over-estimated the prevalence of ACS and PE.  Physicians had a mean and median pretest estimate for ACS of 17% and 9%, respectively, and the software guessed 4% and 2%.  Actual retail price:  2.7%.  For PE, physicians were at mean 12% and median 6%, with the software at 6% and 5%.  True prevalence: 1.8%.

I don’t choose this article to highlight Kline’s algorithm, nor the comparison between the two.  Mostly, it’s a fascinating observational study of how poor physician estimates are – far over-stating risk.  Certainly, with this foundation, it’s no wonder we’re over-testing folks in nearly every situation.  The future of medicine involves the next generation of similar decision-support instruments – and we will all benefit.

“Clinician Gestalt Estimate of Pretest Probability for Acute Coronary Syndrome and Pulmonary Embolism in Patients With Chest Pain and Dyspnea.”
http://www.ncbi.nlm.nih.gov/pubmed/24070658

CTCA Is Better Than Wishing & Hoping

CT coronary angiograms have infiltrated the Emergency Department, with trials such as ACRIN-PA, CT-STAT, and ROMICAT II demonstrating their utility – primarily sensitivity – for the rapid detection of coronary artery disease.  It comes as a surprise to no one that an angiogram demonstrating a total absence of coronary artery disease confers an excellent short-term prognosis.  The downside, of course, is cost, contrast, radiation, and the suggestion that low-risk patients might be harmed by additional, unnecessary testing.  However, enthusiasm for the procedure abounds.

This is an observational study from Thomas Jefferson University looking at consecutive Emergency Department patients referred for CTCA, prospectively collecting variables to calculate TIMI and GRACE risk scores.  No clearly defined primary outcome is provided, but it seems these authors aimed to demonstrate that CTCA would correctly detect severe coronary disease (>70% stenosis) and better prognosticate adverse outcomes than the TIMI and GRACE risk scores.  They enrolled 250 patients, lost 29 to follow-up, and reported six adverse cardiovascular events within 30 days – 2 MIs, 2 ACS, and 2 revascularizations.  All six were TIMI 1 or 2, had relatively middling GRACE scores, and had extensive CAD detected on CTCA.  Overall, 17 patients had significant CAD (>50% stenosis) detected, and increasing TIMI and GRACE scores did not correlate with its presence or absence.  Therefore, these authors feel CTCA is an appropriate diagnostic study and is superior to clinical assessment and risk scores.  They even go so far as to disparage Rita Redberg’s editorial in the New England Journal of Medicine that questioned whether any cardiovascular imaging was indicated before low- and intermediate-risk chest pain patients left the Emergency Department.

They seem, unfortunately, to turn a blind eye to their inability to appropriately select patients for imaging, with only a 6.8% yield for significant stenosis, fewer than half of whom even progressed to a cardiac outcome.  I also take issue with the 2 patients they classified as ACS – they didn’t receive revascularization and didn’t have an MI – so what were they?  Either way, we’re looking at great expense in a cohort with only 1.4-2.4% incidence of positive cardiac outcome within 30 days.  Additionally, the comparison to TIMI and GRACE is a straw-man comparison to instruments proven to have poor predictive value in Emergency Department populations.

This is simply another trip down the quixotic zero-miss path to destruction, even going so far as to fearmonger with liability claim cost statistics.  Rather, it’s clear we’re simply doing a terrible job searching for the needle in the haystack – and the vast majority of these patients are safe for appropriate follow-up after initial Emergency Department assessment.  Rather than use this article to justify admission for CCTA, I would present this data to your patients in the context of shared decision-making and educate them regarding the high costs, abysmal yield, and poor specificity of the test used in this context.

“Cardiac risk factors and risk scores vs cardiac computed tomography angiography: a prospective cohort study for triage of ED patients with acute chest pain”
http://www.ncbi.nlm.nih.gov/pubmed/24035047

Choose Cardiac Testing Wisely

This ought come to no surprise to various proponents of Bayesian reasoning – in the expected sense that outputs of testing individuals with inappropriate pretest probabilities will be garbage.

This is a prospective evaluation of consecutive patients referred for office-based stress myocardial perfusion imaging with single-photon emission computed tomography (SPECT-MPI).  These authors evaluated referring clinician notes and patient histories and stratified 10-year coronary risk, chest pain syndromes, and categorized studies as appropriate, uncertain, and inappropriate.

Of the 1,707 patients referred for SPECT-MPI, 1,511 had complete follow up and were classifiable.  Pre-test appropriateness of referrals varied – but 47% of primary care referrals were inappropriate and 28% of cardiologist referrals were inappropriate, with inappropriate referrals for women patients exceeding men.  The kicker – abnormal MPI in the appropriate-testing group was associated with poorer outcomes, while abnormal tests in the inappropriate-testing group had no such association.

One of the basic principles of diagnostic testing is choosing patients for whom we can have faith in the results.  In our world of flawed tests, when the likelihood of a positive result is low, the balance between true positives and false positive tilts to favor misleading rather than valid diagnoses.  In a minority of instances, these tests may yet be appropriate – but, as we can see, cardiac testing under questionable circumstances provides no true prognostic value.  These are the population costs and harms of our zero-miss culture.

“The Impact of Appropriate Use on the Prognostic Value of SPECT Myocardial Perfusion Imaging”
http://www.ncbi.nlm.nih.gov/pubmed/24021779

Copeptin & Publication Bias

There is a phenomenon in the medical literature called publication bias.  It results from two phenomena – authors are more likely to submit the results of trials with positive results, and editors tend to publish articles with positive results.  This results in all sorts of flaws with regard to the composition of the scientific literature, and exerts a particularly troubling hidden effect in meta-analyses and systematic reviews.

I comment upon this in the context of yet another cardiovascular assay article that has – essentially – negative results that are spun to be positive.  Copeptin, as I’ve discussed before, is another acute phase indicator of myocardial demise – but sacrificing specificity for sensitivity.  These authors combine copeptin with hs-TnT for evaluation of chest pain in the Emergency Department, and report several favorable findings in their abstract and the text of their discussion.

In reality only one of the findings they focus on is truly positive – an increase in sensitivity from 76% to 96%.  The NPV increases from 95% (90.4-98.3) to 98.9% (94.2-100) and is not truly a positive result.  More importantly, the authors report copeptin “adds incremental value” – when the area under the receiver operating curve is statistically identical at 0.886 (0.85-0.922) vs. 0.928 (0.89-0.967).

Perhaps copeptin will someday be proven to add true clinical value in an algorithm for the rapid assessment of chest pain in the Emergency Department.  This paper, however, seems to have exaggerated the positivity of its results.  Considering the spate of other recent “positive” copeptin articles – I foresee systematic reviews and meta-analyses of the test characteristics further perpetuating any unremarkable reported advantage in test characteristics.

“Early rule out of acute myocardial infarction in ED patients: value of combined high-sensitivity cardiac troponin T and ultrasensitive copeptin assays at admission”
http://www.ncbi.nlm.nih.gov/pubmed/23816196

A Lovely Overview of Highly-Sensitive Troponin

Although ranting is fun, I much prefer pointing readers in the direction of useful, educational articles – and dispensing with the lighthearted vitriol.

Today, I don’t have to gripe about JAMA – because they’ve published a succinct and fair assessment of the new highly-sensitive troponins by Dr. Lemos from UT Southwestern.  Written for a general audience, he begins with, essentially, a case example of mismanaged Type II MI resulting from non-specific troponin rise, and then progresses through the various confounding causes of elevated troponins and the definition of myocardial infarction.  He then proceeds to frame these problems in the context of ruling out ACS and balancing sensitivity and specificity, as I’ve previously covered here, here, and here.  He makes a fine point that expanding use of these assays will mean approaching the troponin measurement as a continuous value, rather than dichotomous, and a more nuanced diagnostic process.  He also cautions against over-testing and over-diagnosis in the low-risk population.

He also half-proposes the use of troponin testing in the outpatient setting, as elevated baseline troponin levels are associated with poor prognosis.  However, he notes it remains uncertain the effect routine measurement might actually have on cost-effective care and outcomes.

The author discloses conflict-of-interest with several firms, including manufacturers of the highly-sensitive assays – but his conclusion is quite restrained, and acknowledges the very real practice limitations.

“Increasingly Sensitive Assays for Cardiac Troponins” 
jama.jamanetwork.com/article.aspx?articleid=1693870‎

Misleading Claims for Coronary CTA

The authors of this article make several discrete claims regarding the utility of coronary CT angiography – simply stated right in the title of the article:  “Routine coronary computed tomographic angiography reduces unnecessary hospital admissions, length of stay, recidivism rates, and invasive coronary angiography in the Emergency Department triage of chest pain”.  And, essentially all the assertions made in this observational, retrospective review are suspect.

Reduces unnecessary hospital admissions:
The article in no fashion addresses “unnecessary” hospital admissions.  After all, of their selected cohort of patients, a tiny fraction – 9 of 1,788 – ruled-in for acute MI.  A total of 42 underwent revascularization, but this is a measure reflecting only the aggressiveness of their local cardiology groups.  It would seem the real problem regarding “unnecessary” admissions is an inability to select patients with appropriate clinical probability for further evaluation.

Reduces length of stay:
There is a less than 1 hour reduction in length of stay only for discharged ED patients.  A true accounting of the LOS and congestion of chest pain patients ought to include admitted patients who depart the ED for their hospital observation bed soon after their initial biomarker result – but that would probably make their overall result contrary to their chosen narrative.  The reduction in length of stay is also influenced by the authors exclusion of patients who had ED LOS less than 3 hours – as the authors simply decide no adequate evaluation of low-risk chest pain patients could be performed in that timeframe.

Reduces recidivism rates:
The reduction in recidivism rates may have reached statistical significance, but the absolute difference was only 20 patients, most of whom were discharged from the Emergency Department.

Reduces invasive coronary angiography:
There is a reduction in coronary angiography – mostly, from what I can tell, in that the handful of patients with multi-vessel disease detected on CCTA were referred to CABG, and the use of invasive coronary angiography was obviated.  The absolute difference was only 19 angiography episodes – an avoidance of a handful of $2000-$3000 procedures at the cost of nearly a thousand $700-$1200 CCTAs.

Finally, their abstract conclusion claims it reduces healthcare resource utilization:
The authors never explicitly define this endpoint – which is probably for the best, as I count 960 non-invasive and 8 invasive tests in their CCTA cohort versus 368 non-invasive and 27 invasive tests in their “standard evaluation” cohort.  The admission rate, however, is more than halved from 40% to 14%.  A reduction in resource utilization would be contrary to general consensus from trials of CCTA versus standard care.

Most disturbingly, this article reports “Disclosures: none”.  However, a simple internet search reveals multiple authors having prior relationships with Siemens and GE Healthcare.  Perhaps by some narrowest definition this isn’t untruthful, but it is certainly misleading.

“Routine coronary computed tomographic angiography reduces unnecessary hospital admissions, length of stay, recidivism rates, and invasive coronary angiography in the Emergency Department triage of chest pain”
http://www.ncbi.nlm.nih.gov/pubmed/23684682

Here Comes Copeptin

Are you interested in making your AMI diagnostic evaluation even less specific?  Good!  Because Brahms Thermo Fisher et al want to sell you a rapid copeptin assay to help with that.

Copeptin is a stable, terminal portion of the arginine vasopressin peptide.  This peptide is released from the pituitary in response to cardiovascular hemodynamic stress and has a theoretical role in the diagnosis of acute myocardial infarction.  The advantage copeptin may have over conventional troponin assays is detectable release in circulation preceding troponin.

In 1971 patients collected through their multi-center trial, 156 were diagnosed with AMI (7.9%).  Upon presentation to the Emergency Department, 40 were STEMI.  281 patients had cTnI greater than 40ng/L, 97 of whom were subsequently diagnosed with nSTEMI.  1646 had cTnI less than 40ng/L, 19 of whom eventually were diagnosed with nSTEMI – a miss rate of 1.1%.  Pretty good – but, obviously, we practice in a zero-miss world.  Adding copeptin to this troponin-negative population with a cut-off of 14pmol/L decreased the miss rate to 0.5%.  The specificity, of course, was useless – only 10 of 493 patients with positive initial copeptin and negative inital troponin went on to receive a diagnosis of nSTEMI.

So, the question is – would a negative copeptin change your practice?  Is there a clinically important difference between a 1 in 100 miss rate vs. a 1 in 200 miss rate?  These authors think adding copeptin to troponin will allow you to discharge a patient after the inital biomarker result – but I think this minimal incremental improvement in diagnostic performance doesn’t change whatever pathway the patient was already on, nor add much to a discussion of shared decision-making with the patient.  They also don’t address a performance advantage compared to high-sensitivity troponin assays (which have, of course, their own issues).

These authors are pretty high on copeptin – but, then again, many of them are employed by or sponsored by the manufacturers of the copeptin assay.

“Copeptin Helps in the Early Detection Of Patients with Acute Myocardial Infarction: the primary results of the CHOPIN Trial”
http://www.ncbi.nlm.nih.gov/pubmed/23643595

Questioning “Atypical Angina”

The prevailing notion has been that women present with symptoms of angina that are “atypical” from men – headaches, jaw pain, generalized malaise – rather than definitive anginal-type chest pain or pressure.  These authors would like to suggest this global characterization is incorrect.

These authors enrolled a sample of 128 men and 109 women who underwent coronary angiogram following an abnormal stress test.  Patients with obstructive coronary artery disease on their angiogram were surveyed regarding the symptoms that prompted them to seek care.  Of this cohort, 89 men had obstructive disease compared with 50 women.

Overall, there was no significant statistical difference in the rate of most descriptors used by men or women.  Surprisingly, women were statistically more likely to use “typical” terms such as “discomfort”, “crushing”, “pressing” and “aching” to describe their chest pain.  Therefore, these authors conclude the clinical construct of “atypical angina” in women is incorrect.

I would tend to agree – excepting their study suffers from selection bias.  If patients are only referred for testing due to suspected coronary artery disease, then the population with “atypical” symptoms might not be fully captured.  That being said, it does look as though the female population in their study encompassed a number of patients who potentially were referred for atypical symptoms, considering the yield of their coronary angiography was much lower in women.  It would have been interesting to compare the referral symptoms to the subset with demonstrated obstructive CAD.

“Reconstructing Angina: Cardiac Symptoms Are the Same in Women and Men”
www.ncbi.nlm.nih.gov/pubmed/23567974‎

The Sad Reality of Chest Pain Observations

Chest pain observation units run by the Emergency Department are fairly popular – and it’s easy to see why.  It eliminates the need to fight a hospitalist for admission, allows for complete coverage of medicolegal liability, captures another set of billing codes for ED revenue, and keeps the cardiologists happy with a steady stream of interpretation and consultation revenue.

Duke University has one of these such chest pain observation units, and this study is a retrospective evaluation of the subgroup of patients aged less than 40 years.  Of the 2,231 patients observed for suspected acute coronary syndrome, 362 met eligibility based on age.  Of these 362 patients, median age 36, 238 underwent stress testing and the remainder underwent serial enzymes.

From this cohort, there was a single true positive – defined as a patient who underwent a coronary angiogram with an intervention performed.

There were, however, 14 false positives – indeterminate or positive stress tests and one set of positive biomarkers, leading to five negative invasive coronary angiograms.

The authors sum it up quite nicely:  “The extremely risk- adverse physician cannot totally exclude the possibility of ACS based on age, but it seems that routine observation for such patients may cause the potential for as much harm as good.”

“Utility of Observation Units For Young Emergency Department Chest Pain Patients”
www.ncbi.nlm.nih.gov/pubmed/22975283